Nintedanib developed by Boehringer Ingelheim is a kind of oral triple angiokinase inhibitor which can simultaneously block three growth factor receptors: the endothelial growth factor receptor, the platelet-derived growth factor receptor and the fibroblast growth factor receptor. The blockade of these receptors may lead to inhibition of angiogenesis, which plays a key role in inhibiting tumor growth. The drug used for the treatment of idiopathic pulmonary fibrosis was granted the title of “breakthrough therapy drug” by U.S. FDA for the first time in July 2014, and the trade name of its ethane sulfonate preparation is Vargatef.
The chemical name of Nintedanib: (Z)-{1-[4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino) phenylamino]-1-phenyl-methyl}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate (I); the structural formula as follows:

The preparation method of Nintedanib has been reported, and the synthesis method of Nintedanib and its analogue has been reported in PCT patents WO2001027081 and WO2009071523 from the original company. In this method, the drug is generated through condensation reaction of two key intermediates A and B under the alkaline condition.

Additionally, the synthesis method of intermediates A and B are further reported in the literature J. Med. Chem, Pages 4466-4480, Vol. 52, 2009 and Chinese Journal of Pharmaceuticals, Pages 726-729, Vol. 43, Issue 9, 2012. And based on the optimized reaction condition, reaction sequence, rate of charge and catalyst selection, the synthetic route stated above becomes more simple and reasonable.

By analyzing the structural characteristics of Nintedanib and combination of the current synthesis method of this compound and its intermediates, the applicant finds cis “methylene on indoline ring” structure and its formation method is the key to the whole synthesis process. It is also one of the difficulties. The process from the original company is that through the 3-position substitution and condensation reactions on 2-oxo-indoline ring and trimethyl orthobenzoate under the action of acetic anhydride, the trans “methylene” derivative, namely intermediate A is obtained. The methoxy in intermediate A is used as the leaving group to get a substitution reaction with the anilino in intermediate B, thus generating the target product. The intramolecular hydrogen bond in intermediate A can promote the transformation from “trans” to “cis”.
However, there exist some flaws or weaknesses in the existing process route. For example, the alkylation on the benzene ring easily produces positional isomer due to the impacts from nitryl. The especial case is that the 2-oxo-indoline ring after ring formation must be protected by acylation to achieve the smooth condensation reaction in which methylene is produced. The removal of acylation Pg will affect the functional groups of the other amide in the product, leading to the increased side reactions to reduce yield and quality.

In view of the flaws in the existing process, the development of economical and environmentally friendly preparation technique with simple process can greatly promote the industrial production of the API and improve its economic and social benefits, and in this technique, the seeking for the synthetic route without protection and with deprotection is especially important.